Novel drug delivery device

ABSTRACT

A drug delivery device for administering a drug at a controlled rate for a prolonged period of time to produce a local or systemic physiological or pharmacological effect is comprised of a wall surrounding a reservoir containing a drug. The reservoir is formed of a drug carrier permeable to the passage of the drug and in which the drug has limited solubility. The wall is formed in at least a part of a drug release rate controlling material also permeable to the passage of the drug, but the rate of passage of the drug through the wall is lower than the rate passage of the drug through the drug carrier so that drug release by the wall is the drug release rate controlling step for releasing drug from the drug delivery device.

This is a division of copending application Ser. No. 185,208, filedSept. 30, 1971, and now U.S. Pat. 3,896,819 which in turn is acontinuation-in-part of application Ser. No. 42,786, filed June 2, 1970,now U.S. Pat. No. 3,854,480, which in turn is a continuation-in-part ofapplication Ser. No. 812,116, filed Apr. 1, 1969, now U.S. Pat. No.3,598,122 and application Ser. No. 864,175, filed Oct. 6, 1969, nowabandoned.

BACKGROUND OF THE INVENTION

This invention relates to a novel and useful drug delivery device forreleasing drug at a controlled rate for a prolonged period of time toproduce a local or systemic physiological or pharmacological effect. Thedrug delivery device is comprised of a reservoir surrounded by a wall.The reservoir is comprised of a drug within a carrier permeable to thepassage of the drug and in which the drug has limited solubility. Thewall of the device is comprised in at least a part of a drug releaserate controlling material permeable to the passage of the drug. Both thecarrier and the wall are permeable to the passage of drug, as bydiffusion, but the permeability of the wall to the drug is lower thanthe permeability of the carrier to the drug. Accordingly, drug releasethrough the wall is the drug release rate controlling step for releasingdrug from the drug delivery device of the invention.

the terms and phrases such as "reservoir", "carrier", "drug", "limitedsolubility", and the like that appear throughout the specification andthe accompanying claims are defined in the specification in the sectionentitled, "Detailed Description of the Invention."

In many therapeutic programs pertaining to the management of health anddisease, it is desirable and indicated to use a drug delivery device toprovide for the slow release of a drug to the body at a controlled rateover a prolonged period of time to achieve a desired physiologic orpharmacologic effect. In many instances, such a rate of release of thedrug from a drug delivery device should have a zero order timedependence, that is, the rate of drug release is independent of time.

Different approaches have been tried by the prior art to obtain such adrug delivery device. One approach, which has received great attention,is to mix a drug with a carrier material that is gradually broken downby body fluids with the drug released as the carrier disintegrates.Numerous carriers have been used in such devices including waxes, oils,fats, soluble polymers, and the like. While some of these devices haveprovided for a delayed release of the drug, the desired constant releaserate for a prolonged period has not been obtained. One reason for thisis that as the carrier disintegrates the surface area of the dosage unitdecreases, concomitantly exposing increasingly smaller quantities of thecarrier to the surrounding body fluids. This inherently results in adecline in the release rate over time.

Another approach to this problem has been to disperse the drugthroughout a solid matrix material through which the desired amount ofthe drug is released by diffusion. But, this type of drug deliverydevice has proven incapable of providing a zero order drug release rate,because of the drawback that the release rate (dM_(t) /dt) instead ofbeing zero order (dM_(t) /dt = constant) decreases with time (dM/dt =constant x t.sup.×⁻) during much of the drug release history; J. Pharm.Sci., Vol. 52, pages 1145 to 1149, 1963.

Still another approach has been to enclose the drug within a singlecapsule having a polymeric wall or walls through which the drug canpass, for example, by diffusion. An approach of this kind is set forthin U.S. Pat. No. 3,279,996. These devices too, have inherentdifficulties. One difficulty encountered is that small devicescontaining a small amount of dry, powdered drug are hard to fabricatebecause the device can be manufactured from only a few materials andfurther because the materials having the drug must be non-toxic as theycontact the body. Additionally, these prior art devices have generallybeen based on the use of a single material, such as silicone rubberpolymers, especially polydimethylsiloxane, as the diffusion controlmembrane. In large part, these polymers were selected because of theirpermeability to some important drug molecules. But, it has been foundthat mere high permeability without consideration of release ratecontrolling properties can be a significant disadvantage which defeatsthe primary object of an acceptable drug delivery device. Thus, withmany important drug molecules, such as progesterone, the diffusion ratethrough a polydimethylsiloxane membrane is very great, and it is oftengreater than the rate of clearance of the diffused drug from the outersurface of the capsule. In many instances this results in the ratelimiting step being clearance of the drug from the exterior of thecapsule, rather than diffusion through the capsule wall. Clearance ratewithin the body is difficult to control, as it is subject to frequentchange, and this inherently defeats the objects of providing a drugdelivery device which releases drug at a constant rate over prolongedtime.

In my copending application, U.S. Ser. No. 42,786 filed June 2, 1970,and assigned to the assignee of this invention, there is described adrug delivery device comprised of a drug dispersed in a solid matrixpermeable to passage of the drug and surrounded by a membrane, alsopermeable to passage of the drug but at a lower rate than through thematrix. That device has proven itself capable of zero order drug releaseand represents a substantial improvement over previously proposed drugdelivery devices. However, in some instances, when zero order drugrelease is required for long periods of time, on the order of severalmonths to a year or more, it may not be attained with the device of thatcopending patent application. Thus, it has been found that as drug isreleased by that device there is created over time a space in the solidmatrix drug carrier which if not occupied by more drug can result in thecarrier contracting and moving away from the membrane. The loss ofcontact between the carrier and the membrane at the carrier/membraneinterface tends to decrease the availability of drug at the interfacefor release by the membrane. Thus, since the amount of drug available tothe membrane is no longer constant, drug is released from the device ata continually reduced rate and the device does not maintain a constantzero order release rate. For applications in which controlled release isdemanded for very long periods, this can be a problem.

It is also known to the art to incorporate drug into certain types ofliquid carriers, usually in microcapsule formulations, for example. U.S.Pat. No. 3,464,413. However, these microcapsules are not designed forthe controlled release of drug for a prolonged period of time by usingdrug release rate controlling materials. The mirocapsules are frequentlycrushable, and they merely function as drug carriers supplying theirdrug in bulk, and not in controlled amounts by rupture of themicrocapsules. Therefore, these types of capsules are not suitable forreleasing drug at a controlled rate for a prolonged peroid of time.

SUMMARY OF THE INVENTION

Accordingly, it is an immediate object of this invention to provide adrug delivery device for the administration of locally acting orsystemically acting drugs to produce a physiologic or pharmacologiceffect which device overcomes the aforesaid disadvantages associatedwith the prior art modes of administration devices.

Still another important object of the invention is to provide a drugdelivery device for releasing drug at a controlled rate for a prolongedperiod of time.

Yet still another object of this invention is to provide a drug deliverydevice which can release drug at a rate which does not vary with time.

Still yet another object of the invention is to provide a reliable andeasily used drug delivery device for continuously administeringcontrolled quantities of drug to the body or to drug receptor sites.

A further object of this invention is to provide a complete dosageregimen for a particular time period, the use of which requiresintervention only for initiation and termination of the regimen.

In accomplishing these objects and advantages of this invention, onefeature of the invention, in its broadest aspect, resides in a noveldrug delivery device comprising a wall enclosing a reservoir. Thereservoir is comprised of a drug within a liquid carrier permeable tothe passage of the drug, as by diffusion, and having limited solubilityfor the drug. The wall surrounding the reservoir is comprised in atleast a part of a drug release rate controlling material permeable tothe passage of the drug, as by diffusion, but at a lower rate thanthrough the liquid carrier. The wall is supplied with drug by passage ofdrug from the carrier. Drug entering the drug release rate controllingmaterial comprising the wall passes therethrough for administration tothe body or to a drug receptor site. Since the permeability of thecarrier to the drug is always higher than the permeability of the drugrelease rate controlling material, the passage of drug through the wallis the rate determining step for drug release from the drug deliverydevice.

Other objects, features, and advantages of the invention will beapparent to those skilled in the art from the detailed description ofthe invention which follows, taken in conjunction with the drawings, andthe accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but rather are set forthto illustrate various embodiments of the invention, the drawings are asfollows:

FIG. 1 is a perspective, cross-sectional view of a drug delivery deviceof the invention depicting a wall surrounding a reservoir;

FIG. 2 is a cross-sectional view of the drug delivery device of FIG. 1depicting drug contained in the reservoir;

FIG. 3 is a side, fragmentary view depicting an anal drug deliverydevice of the invention for releasing drug in a body orifice;

FIG. 4 is an elevational view of a drug delivery tampon embodying theprinciples of the invention;

FIG. 5 is a frontal, fragmentary view of a uterine cavity showing a drugreleasing intra-uterine device positioned in the cavity;

FIG. 6 is a schematic drawing showing a drug delivery implant fabricatedin accordance with the invention;

FIG. 7 is a schematic illustration of a drug delivery device shaped as aperoral tablet prepared according to the invention;

FIG. 8 is an isometric view of a catamenial drug delivery device formedof multiple parts, as manufactured according to the spirit of theinvention;

In the drawings and specification, like parts in related figures areidentified by like numbers. The terms appearing earlier in thespecification and in the description of the drawings, as well asembodiments thereof, are further described elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawings in detail, which are examples of variousdrug delivery devices of the invention, and which examples are not to beconstrued as limiting, one embodiment of a novel drug delivery device isindicated in FIGS. 1 and 2 by the number 10. Drug delivery device 10 iscomprised of a wall 11 surrounding a reservoir 12. Reservoir 12 iscomprised of a drug carrier 13 as shown in both FIGS. 1 and 2 and asfurther shown in FIG. 2 drug carrier 13 contains a drug 14, or a mixtureof drugs. Drug carrier 13 is a liquid carrier, a description of which ispresented later in the disclosure and it is permeable to the passage ofdrug 14, as by diffusion or by convection. Additionally, anotherimportant aspect of drug carrier 13 is that drug 14 has a limitedsolubility therein. Wall 11 is formed of a drug release rate controllingmaterial permeable to the passage of drug, as by diffusion, but the rateof passage of the drug through the wall is lower than the rate ofpassage of drug through the drug carrier. In operation, drug carrier 13serves as a reservoir by supplying dissolved drug 14 to wall 11 as drugmolecules move through the carrier to bathe the inner surface of wall11. Drug 14 present at the drug carrier/wall interface dissolves in andmigrates through wall 11, ultimately reaching the outer surface of wall11. As drug 14 leaves drug carrier 13, undissolved drug present inreservoir 12 dissolves in carrier 13 to maintain a constant supply ofdissolved drug in the carrier for continuously supplying drug atsubstantially the same rate to wall 11. Wall 11 operates to effectivelycontrol the rate of release of drug throughout the useful period of drugrelease from the device. Thus, a zero order drug release rate can beobtained.

Wall 11 of device 10 is comprised of a drug release rate controllingmaterial permeable to the passage of drug 14, as by diffusion. Thematerial used to make wall 11 can have uniform properties across all itsdimension, or it can be microporous, or it can be a material possessingboth of these properties. When wall 11 is made from the former material,that is, a material that is substantially imperforate, molecules of drug14 dissolve in and diffuses through wall 11 by the process of diffusion.When wall 11 is made from the latter material, that is a material havingmicroporous properties, molecules of drug 14 diffuse through a liquidphase, not shown, present in the minute pores, pinholes, or cracks, forexample, by absorption of body fluids by a hydrophilic microporousmaterial, by diffusion. When wall 11 is made from a material having bothof these properties, drug 14 can be released from device 10 through wall11 by a concurrent operation of both of these mechanisms, that is, byboth diffusion through wall 11 and by diffusion through liquid in thepores of wall 11. In the specification, the permeation mechanism of drugrelease through the drug release rate controlling material isgenerically described as " by diffusion" for both types of materialsused to fabricate wall 11. The permeability of wall 11 to the diffusionof drug 14 is lower than the permeability of liquid drug carrier 13 tothe diffusion of drug 14 and passage through wall 11 thus acts as therate limiting step for drug release from device 10.

FIG. 3 illustrates another drug delivery device of the invention. InFIG. 3, a drug delivery device 10 designed for administering drug withina body opening is shown positioned in a body having an anal canal 16located between the buttocks and terminating in an anus 17. Drugdelivery device 10 of FIG. 3 is comprised of a wall 11 surrounding areservoir 12. Reservoir 12 is comprised of a drug carrier 13 containingdrug 14. Drug carrier 13 is liquid in nature. Drug carrier 13 ispermeable, as by diffusion, or convention or both, to the passage ofdrug 14, which has limited solubility therein. Wall 11 is made of a drugrelease controlling material permeable to the passage of drug 14, as bydiffusion, and it releases drug from the device at a predetermined,controlled rate within the body. In this device, as with the devicediscussed above, drug released from carrier 13 is replenished byundissolved drug dissolving in carrier 13 to insure that drug iscontinuously available to wall 11. Also, in the device of FIG. 3,release of drug through the wall is the rate controlling step forrelease of drug from this device.

FIG. 4 illustrates another drug delivery device of the invention. FIG. 4shows a drug delivery device 10 shaped as a vaginal tampon of anelongated, generally cylindrical shape. One end 29 of the tampon isrounded while the opposite end 18 is flat for easy insertion of the drugdelivery device into a vagina. The drug delivery tampon is equipped witha manually controlled cord 19 for easily removing the drug deliverytampon from the vagina after the desired degree of medication has beenachieved. The drug delivery device 10 is comprised of a reservoir 12containing a carrier medium 13 with a drug 14 dissolved therein. Carriermedium 13 is a liquid or liquid like solution or medium and drug 14 haslimited solubility therein. Carrier medium 13 also contains undissolveddrug that will dissolve in the carrier after the drug presentlydissolved therein leaves the carrier. Reservoir 12 is confined within awall member 11 that forms the supportative structure, or main body ofdevice 10. Both the carrier medium and the wall are manufactured frommaterials that are different and are permeable to the passage of drug,but, the permeability of the carrier to the passage of drug is alwayshigher than the permeability of the wall to the passage of drug. Wall 11therefore is the rate controlling means for releasing drug from thedevice. Wall 11 is permeable to the passage of drug as by (1) diffusionthrough a homogenous wall (2) as by diffusion through micropores in thewall, that is, by diffusive flow through a media contained therein, or3) both. In actual operation, drug is released from carrier medium 13that is in intimate contact with wall 11 to the wall and through thewall at a controlled rate of release from the drug delivery device. Asdrug leaves the carrier, undissolved drug in the reservoir dissolves inthe carrier thereby continuously supplying the wall with drug foradministration at a zero order rate into the vagina to achieve a desiredphysiological or pharmacological benefit.

In FIG. 5 there is graphically depicted an intrauterine contraceptivedrug delivery device prepared according to the spirit of the invention.Drug delivery device 10 comprises a wall 11 permeable to the passage ofdrug, as by diffusion, housing a reservoir 12. Device 10 it will be seenconsists of two continuous loops 20 and 21 each having a cross-sectionaldiameter of about 1.5 to 2.5 cm. Loop 20, the larger of the two loops,is adapted to be located within the uterine cavity 22 and it contactsthe sides 23 as well as the fundus uteri 24 of uterus 25. Loop 21, thesmaller loop, is positioned in the neck 26 of uterus 25 for assisting inmaintaining device 10 within uterus 25. Reservoir 12 is comprised of acarrier medium 13 containing a drug 14. Carrier medium 13 can be aliquid, gel, sol or the like, and a description thereof is presentedlater in the disclosure. The carrier confined in the reservoir servesseveral purposes for effectively releasing drug from the device. First,it is permeable to the passage of drug so that drug in the carrier canmigrate to wall 11. Secondly, the carrier contacts and bathes the innersurface of wall 11 for facilitating drug transfer from the carrier tothe wall so that drug molecules can dissolve in and migrate through thewall to the outer surface thereof. Thirdly, the carrier acts as aconstant source of drug and it has a limited, or varying degrees ofsolubility for drug or a mixture of drugs. The carrier is formulated tocontain both dissolved and undissolved drug, and they can behomogenously or heterogenously dissolved and/or dispersed therein. Thus,the carrier is a constant source of drug because, as drug dissolves inthe carrier and transfers from the carrier to the wall, undissolved drugdissolves in the carrier to insure a constant and uniform supply druguntil essentially all the drug has been released by the device. Thismechanism of continually replenishing the drug enables the device toachieve a uniform, release rate for the device throughout its use.

Wall 11 of the intrauterine contraceptive drug delivery device 10, isformed of a drug release rate controlling material to continuously meterthe flow of an effective amount of a drug from the reservoir for releasewithin the uterus. The rate of drug release through the wall is lowerthan the passage of drug through and/or from the carrier, so that theformer is the rate controlling step for drug release from the device.The depicted intrauterine drug delivery device is manufactured in anon-traumatising design for easy insertion into the uterine cavity. Thedevice can be fabricated into assorted sizes, shapes, and thicknessesfor adaptation to a wide variety of uteri.

In FIG. 6, there is illustrated a drug delivery device 10 for use as adepot implant comprising a wall 11 surrounding a reservoir 12 containinga drug 14 dissolved in a drug solubilizing limited carrier 13. Both thesolubilizing limited carrier and the wall are permeable to the passageof drug, as by diffusion, but the rate of drug passage through the wallis lower than through the carrier, so the wall thus acts as the ratelimiting barrier for drug release. Drug delivery implant 10 may be ofany shape that is adapted for implantation. The implant, as shown, is ofcylindrical construction with a view of a longitudinal section throughthe implant. The implant drug delivery device may be implanted withinthe body for the purpose of metering to the body at a constant anduniform rate drug for producing any desired medical or pharmaceuticalresult.

FIG. 7 represents a schematic drawing of a pill or tablet peroral drugdelivery device 10 of the invention. This device 10 comprises a wall 11formed of a material permeable to the passage of drug, as by diffusion,and having enclosed therein a reservoir 12 (shown in opened section)containing a drug 14 in a drug solubilizing limited carrier phase 13.Carrier 13 is fabricated of a non-solidified material permeable to thepassage of drug, but the rate of passage of drug is higher in it than isthe rate of passage of drug through the wall. The pill or tablet drugdelivery devices are suitable for oral administration for continuouslymetering a flow of an effective amount of drug over a prolonged periodof time to the gastrointestinal tract.

FIG. 8 represents a drug delivery device 10 of catamenial shapecomprised of a wall surrounding a reservoir in which at least a part ofthe wall is formed of a drug release rate controlling material permeableto the passage of the drug. Device 10 is comprised of a top wall 11permeable to the passage of the drug as by diffusion, and it has a shapegenerally approximating the shape of the exterior surface of the pubicarea to which it is to be applied. The remainder of the wall forming thedevice, side wall 26 and the bottom wall 26, shown in open section, aremade from wall forming materials that are impermeable to the passage ofdrug. Collectively, the top, side and bottom walls surround a reservoir12, shown in section, that comprises a drug solubilizing limited carrier13 permeable to the passage of drug 14. Drug 14 in carrier 13 can be ina dissolved state, partially dissolved state or undissolved drug state.Drug 14, shown as dots on the surface of wall 11, is drug thattransferred from the carrier to top wall 11, by first dissolving thereinand then diffusing through the wall to its exterior surface. Thecatamenial is provided at its ends with tabs 27 for securing thecatamenial in position on the body of the wearer, and also formaintaining it there during delivery of the drug by the drug deliverydevice. In the device, the diffusion of drug through drug carrier 13 isat a higher rate than through the drug release rate controlling materialof wall 11 so that passage through the wall member is the drug releaserate controlling step for the device for administering drug to thewearer.

While the above FIGS. 1 through 8 inclusive are illustrative of variousdrug delivery devices that can be made according to the invention, it isto be understood that these drug delivery devices are not to beconstrued as limiting, as the drug delivery devices of the invention cantake a wide variety of shapes, sizes and forms for administering thedrug at controlled rates to different areas of the body or to differentdrug receptor sites. For example, the invention includes external andinternal drug delivery devices such as skin patches, sublingual orbuccal drug delivery devices, peroral devices, arterial devices, nasaland ear drug delivery devices, ocular inserts, suture materials, plasticheart valves, Stan-Edwards heart valves, hip joints, non-thrombogenichydrocephalus shunt, bone pins, pessaries, prosthesis, artificialglands, cervical rings, troches, intrauterine drug delivery devices ofcylindrical, bullet, elliptical, circular, bulbous, loops, bows, or anyother geometrical shape that readily lends itself to intrauterineplacement such as Birnberg's Bow in U.S. Pat. No. 3,319,625; Comet inU.S. Pat. No. 3,256,878; Majzlin Spring in U.S. Pat. No. 3,397,691;Inhiband in U.S. Pat. No. 3,323,520; Lippes' Loop in U.S. Pat. No.3,250,271; Bakunin in U.S. Pat. No. 3,405,711; in U.S. Pat. No.3,077,879; the ring with tail; Ota ring, and the like. In each instance,all of the drug delivery devices made according to the invention have areservoir comprised of a drug and a liquid drug carrier permeable to thepassage of drug as by diffusion, or convection and also having limitedsolubilizing properties for the drug. The reservoir is surrounded by awall, at least a portion of which is permeable to the passage of thedrug by (1) diffusion, or (2) diffusive flow, or (3) by both. The drugrate of release through the wall is lower than the rate of passagethrough the carrier, so that the drug release rate through the wall isthe drug release rate controlling step. Also, all of the drug deliverydevices are of appropriate known shapes and sizes for implantation,insertion or positioning in the desired body cavities or on tissues foradministering of drug to the body or to a drug receptor site.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of the present invention, it has nowbeen found that the drug delivery device of the invention provides manyimportant advantages over previously known drug delivery devices. Oneadvantage of the device is the ease of construction of the drug deliverydevice by standard manufacturing techniques into devices of varioussized, shapes and forms for delivering drugs to a recipient. A moreimportant advantage of the claimed drug delivery device is to provide abroad range of drug release rates by providing one or more deviceshaving a reservoir, or more than one reservoir in a large multi-purposedevice, wherein the reservoir contains a carrier or a mixture ofcarriers having limited solubility for a drug or a mixture of drugs andwhere the carrier simultaneously releases drug and dissolves replacementdrug to maintain a constant supply of drug for release by the device.

Another important advantage of the invention resides in the drugdelivery devices' ability to effectively control the rate of release ofthe drug from the devices by providing a zero order (dm_(t) /dt -constant) rate of drug release throughout the major portion of the drugrelease history. Yet another important advantage for the drug deliverydevice is its ability to administer drug from the device according to apredetermined drug time release pattern, for example, by providing adrug release pattern that is sinusoidal, parabolic, and the like. Thedrug time release pattern for the device of the invention is obtained bya selection of the drug release parameters, such as, the thickness ofthe material forming the wall, the nature of the material forming thewall, the nature of the drug carrier in the reservoir, and the kind ofdrug contained therein.

The above advantages and objects are achieved by the unique constructionand operation of the device and its ability to transfer drug to arecipient or to a drug receptor site. In construction, the device can beviewed as a single unit constructed device comprising two structuresacting in concert for effective drug administration to a host. Onestructure pertains to a wall comprising the device and formed of a drugrelease rate controlling material permeable to the passage of drug andthe other structure relates to a reservoir comprising a drug carrierphase formed of a material permeable to the passage of drug. Thematerials forming the wall and the drug carrier phase comprising thedevice are chemically and structurally different within a single deviceand the rate of release of drug through the wall is lower than the rateof passage of drug in the drug carrier phase.

These two structures, comprising the unit drug delivery device, operateto effectively transfer drug from the device by first transferring drugfrom the carrier to the wall, and secondly, by transferring drug throughthe wall to a drug recipient. The transfer of drug through the wall canoccur by two different processes or drug transfer mechanisms. These drugtransfer processes are the diffusion process of a drug through a uniformmaterial and by diffusion of drug through the media present in themicropores of a material, as hereinafter described. Thus, for example,drug can be transferred from the carrier to the wall and then throughthe wall by diffusion to the drug recipient, or drug can be transferredfrom the carrier to the wall and then through micropores of the wall bydiffusion to the drug recipient. With the devices of this invention,drug can be transferred by using a combination of these mechanisms fortransferring drug through the wall. Thus, by fabricating devices havingdifferent kinds of walls made from different materials, the device canprovide for transfer of drug through the wall by either diffusion in asubstantially homogenous material or by diffusion in a microporous wall.The wall of the drug delivery device is made from a material that has alower drug release rate than the rate of passage of drug through thedrug carrier to ensure that release kinetics of the device arecontrolled by the release rate of drug through the wall. Thus, bychoosing the wall, a zero order release of drug, or a time releasepattern of drug to the body or drug receptor site can be achieved.

In the diffusion process, the wall is formed from a drug release ratecontrolling material that is permeable to the drug to permit passage ofthe drug by diffusion through the material at predetermined rates. Inthis process, the drug dissolves and equilibrates in the wall surface,and then diffuses in the direction of lower chemical potential. At thesecond boundary equilibrium is again established. When the boundaryconditions on both sides of the wall are maintained constant, a steadystate flux of the drug will be established which can be described byFick's Law of Diffusion. The rate of passage of drug through the wallmaterial is generally dependent, in the case of diffusion, on thesolubility of the drug therein, as well as on the thickness of thematerial. This means that selection of appropriate materials forfabricating the wall will be dependent on the particular drug to beused. By varying the composition and thickness of the wall, the dosagerates per area of the device can be controlled for this material acts tometer the diffusion of drug from the reservoir. In the devices of thisinvention, the materials comprising the wall are chemically and/orstructurally different than the material comprising the drug carrier ofthe reservoir. The drug carrier of the reservoir is permeable to thepassage of drug, but the rate of diffusion or passage through the wallis lower than the rate of diffusion or passage through the drug carrier,so that the rate of passage of drug through the wall is the rate releasecontrolling step for the device. Thus, through this invention, devicesof the same surface area, functioning by diffusion, can give differentdosages of a drug by varying the characteristics of wall to givecontrolled administration of a drug.

In the devices of the invention, when the wall is formed from a drugrelease rate controlling microporous material that is permeable to thedrug, the drug transfer mechanism is by diffusive permeation through themicropores at a controlled and predetermined rate. This drug transfermechanism is diffusion, and it is sometimes referred to as diffusiveflow. It is generally referred to in the specification as diffusion.Generally, in this process the rate of permeation or the rate of drugrelease through the wall is governed by diffusion of the drug through adiffusive medium present in the pores, microholes and cracks of thematerial forming the wall. The diffusive medium, in one embodiment, is aliquid phase comprised of a solution, a colloidal solution, asuspension, or a sol, and the solution can be polar, semi-polar ornon-polar. In these diffusive mediums, the drug can have differentdegrees of solubility, such as fully soluble, partially soluble and thelike, to act in cooperation with the material for achieving a controlleddrug release rate.

The diffusive medium can be added to the material by methods well knownto the art, for example, by immersion of the material in a bathcontaining the diffusive medium to let the medium partially fill orfully saturate the micropores of the material. Another method forcharging the micropores with a diffusive medium is to first add to thereservoir a diffusive medium, or a mixture of diffusive media so thatthe medium can flow from within the reservoir into the pores and remaintherein to permit diffusive flow of later added drug, but not itssolubilizing limited carrier, to flow therethrough. The diffusive mediumsuitable for the immersion purpose are those well known to the art suchas water, glycerin, ethylene glycol, propylene glycol, castor oil, oliveoil, alcohols of 2 to 10 carbon atoms, halogenated hydrocarbons having 2to 20 carbon atoms, aldehydes, and ketones having 4 to 10 carbon atoms,syrups, and the like. Additionally, the diffusive medium can beemulsifying and suspending agents such as methyl cellulose mixed withwater, mixtures of propylene glycol monostearate and oils, gumtragacanth and water, assorted waxes and the like. Representativemediums are set forth in Remington's Pharmaceutical Science, pages 246to 269 and 1338 to 1380, 1970, published by Mack Publishing Company,Easton, Pa.

The diffusive medium, in another embodiment, can be added to the poresof the material forming the wall by locating the wall in a fluidenvironment, for example, by contacting the device with a body tissue,for example, the mucous membranes of the anus, mouth or vagina, that canmake available its intracellular and/or extra-cellular body fluid forsubsequent transfer into the micropores of the wall for functioning as adiffusive medium for the drug. Additionally, the drug delivery devicecan be positioned in a body fluid, for example, in the fluid present inthe stomach of farm animals, the avian cloaca, and the like, for usingthe fluid contained therein, as above described, as a diffusive medium.In another embodiment, the pores can be filled with plasticizer byimmersing the wall in a plasticizer solvent composition, and removingthe solvent in vacuo after the filling of the pores. Exemplaryplasticizers suitable for employment of the present purpose are thecommercially available plasticizers conventionally used for themanufacture of polymeric materials such as diethyl adipate, di-isobutyladipate, di-n-hexyl adipate, di-isooctyl adipate, di-n-hexyl azelate,di-2-ethylhexylazelate, ethylene glycol dibenzoate, acetyl tri-n-butylcitrate, epoxidized soy bean oil, glycerol monoacetate, diethyleneglycol dipelargonate, propylene glycol diluarate, isooctyl palmitate,triphenyl phosphate, and the like.

The materials comprising the wall are chemically and/or structurallydifferent than the materials comprising the carrier. Both of thematerials are permeable to the passage of drug but the rate of flowthrough the wall is lower than the rate through the carrier. Thus, therate of passage of drug through the wall is the rate release controllingstep for the device. Generally, for the practice of this invention, theratio of the drug release rate through the drug carrier of the reservoirto the drug release rate through the wall should be from 100:1 to 2:1and preferably from 10:1 to 2:1. Of course, the invention is not limitedto these release rates as the invention comprises lower or higherrelease rates from the drug carrier and lower and higher rates throughthe wall with the release rate of the wall lower than the release rateof the drug carrier. Thus, the invention provides that devices of thesame surface area, activated by diffusion, can give different dosages ofa drug by varying the characteristics of the wall material to givecontrolled administration of a drug; Encyclopedia of Polymer Science andTechnology, Vol. 9, pages 794 to 807, 1968.

For either of the above discussed mechanisms, diffusion through amaterial, or diffusive flow through a diffusion medium present in amaterial, the transfer or rate of release of drug through the wall is ata lower rate than the rate of release of drug from the drug carrier ofthe reservoir for administration to the body or to a drug receptor site.Thus, the passage of the drug through the wall is the drug release ratecontrolling step for the drug delivery system. In addition, because thereservoir serves to transfer drug molecules to all areas of the wall,the wall of the drug delivery system housing the reservoir remainssubstantially at the thermodynamic activity corresponding to that of thedrug until substantially all of the drug has been released from thereservoir. Ordinarily, one would expect drug migration from thereservoir to cease when sufficient drug has entered the wall toestablish an equilibrium; however, when the drug delivery system is incontact with body tissues or fluids, drug molecules are continuouslyremoved from the outer surface of the wall. For optimum results, therate of release of the drug through the wall should be less than therate of clearance of migrated drug from the external surface of thedevice. This ensures that the drug administration rate is dependent onthe rate of release of drug through the wall which can be controlled,rather than upon clearance of drug from the device in vivo, which canvary. Thus, in contrast to previously proposed drug delivery devices,the rate of release of the drug from the device of the invention canremain essentially constant until the drug delivery device hassubstantially completed its useful function.

The term "reservoir" as used in the specification and the accompanyingclaims generally refers to a "drug carrier" or to a "medium containingdrug," that constantly bathes the inner surface of the drug release ratecontrolling wall and supplies drug thereto. That is, the reservoir iscomprised of a drug carrier material containing dissolved drug, and/orundissolved drug, and/or a mixture of both, and it is a material that ispermeable to the passage of the drug as by diffusion or convection. Thedrug carrier medium used for the purpose of the invention is a liquid,and it can be inorganic or organic, and of naturally occurring orsynthetic origin. Examples of carriers comprised within the terms liquidare, for example, solutions, immiscible liquids, emulsions, gels, sols,colloids, oils, syrups, suspensions, dispersions, liquid pre-curedpolymers, liquid polymers, liquid plasticizers, liquid thixotropicagents, polar solvents, simipolar solvents, nonpolar solvents,liquid-like mediums, mixtures thereof, and the like. Further, for thepurpose of this invention, the terms liquid and the examples thereof aredeemed as functional equivalents and they can be generically termed"liquid core."

The drug carrier medium comprising the reservoir, also has in additionto the properties described supra, limited solubility for contained drugor for a mixture of drugs. By limited solubility is meant that drug issoluble in given amounts in the carrier, that is, it comprises varyingconcentration of drug dissolved in the carrier. Essentially, there isalso an excess amount of undissolved drug present in the carrier. Thesevarying limited solubility concentrations include solubilities such as,soluble, sparingly soluble, slightly soluble, very slightly soluble, andalmost practically insoluble. Generally, on a weight basis at 25° C, theamount of drug dissolved in a carrier that is termed a soluble carrieris about 1 part of drug to about 10 to 25 parts of carrier, the amountof drug dissolved in a carrier that is sparingly soluble for the drug is1 part of drug to about 25 to 100 parts of carrier, from 100 to 1000parts of carrier for 1 part of drug when the drug is slightly soluble inthe carrier, from 1000 to 10,000 parts of carrier for 1 part of drugwhen the drug is very slightly soluble in the carrier, and from 10,000to 15,000 parts of carrier for 1 part of drug in a carrier that isalmost practically insoluble for the drug. Hence, the term limitedsolubility comprises a range of solubility of drug in carrier of 1 partof drug to about 10 to 15,000 parts of carrier on a weight basis at 25°C. The above ranges are set forth to aid in defining the invention, andthey should not be considered as limiting as other ranges at higher orlower temperatures are embraced within the above presentation are alsoincluded herein. The amount of undissolved drug incorporated in thereservoir will vary depending on the type of drug delivery device, theparticular drug, the desired therapeutic effect, and the rate of releaseof desired drug from the reservoir. That is, there is no critical upperlimit on the amount of undissolved drug incorporated in the reservoir,since, it serves as a reserve source of drug for replacing released drugby dissolving in the drug carrier to make drug continually availablefrom the carrier to the wall during the history of the device, or untilthe device is no longer used. The lower limit will depend on theactivity of the particular drug and the time span of its release fromthe device. Generally, the amount of undissolved drug initially presentin the reservoir will range from about 90% by weight to about 99.9% byweight, of the total amount of drug present in the reservoir.

The materials suitable for fabricating the wall of the device aregenerally those materials capable of forming walls, with or withoutpores, through which the drug can pass at a controlled rate of releaseby the process of diffusion or diffusive flow. Such materials arereferred to in this specification and the appended claims as "drugrelease rate controlling materials." Suitable materials for forming thewall are naturally occcurring or synthetic materials, preferablymaterials that are biologically compatible with body fluids, tissues ororgans, and essentially insoluble in body fluids with which the devicewill come in contact. Generally, the use of rapidly dissolving materialsor materials highly soluble in body fluids is to be avoided sincedissolution of the wall of the device would affect the constancy of thedrug release, as well as the capability of the system to remain in placefor certain uses for prolonged periods of time.

Exemplary naturally occurring or synthetic materials suitable forfabricating the wall are drug rate release controlling materials such aspoly(methylmethracrylate), poly(butylmethacrylate), plasticized orunplasticized poly(vinylchloride), plasticized nylon, plasticized softnylon, plasticized poly(ethylene terephthalate), natural rubber,poly(isoprene), poly(isobutylene), poly(butadiene), poly(ethylene),poly(tetrafluoroethylene), poly(vinylidene chloride),poly(acrylonitrile), cross-linked poly(vinylpyrrolidone),poly(trifluorochloroethylene), poly (4,4'-isopropylidene diphenylenecarbonate), and the like. Also, by way of non-limiting example,copolymers such as ethylene-vinylacetate, vinylidene chlorideacrylonitrile, vinyl chloride diethyl fumarate and the like. Examples ofother materials include silicone rubbers, especially the medical gradepoly(dimethylsiloxanes), and silicone-carbonate copolymers; hydrophilicpolymers such as the hydrophilic hydrogels of esters of acrylic andmethacrylic acid as described in U.S. Pat. Nos. 2,976,576 and 3,220,960and Belgian Pat. No. 701,813, modified insoluble collagen, cross-linkedpolyvinylalcohol, cross-linked partially hydrolyzed polyvinylacetate,and surface treated silicone rubbers as described in U.S. Pat. No.3,350,216. Other polymeric membranes hat are biologically compatible anddo not adversely affect the drugs can be used.

Additionally, other materials permeable to the passage of drug suitablefor the present purpose include copolymers such as acrylonitriledithioglycidol, acrylonitrile ethylene oxide, poly(vinyl butyral)comprised of 11% to 45% free hydroxyls, anisotropic permeablemicroporous membranes of ionically associated polyelectrolytes, thepolymers formed by the coprecipitation of a polycation and a polyanionas described in U.S. Pat. Nos. 3,276,589; 3,541,005; 3,541,006;3,546,142; and the like; treated aliphatic polyamide membranes as inU.S. Pat. Nos. 2,071,253; 2,966,700; 2,999,296; and the like; vinylidenechloride vinyl chloride copolymer 40/60 and 10/90; vinyl chlorideacrylonitrile copolymer 80/20, 75/25, 50/50 and the like; vinylidenechloride acrylonitrile copolymer 60/40 and 12/88; water insolublenatural gums, and the like. Also, materials such as regeneratedcellulose, cellulose diacetate, cellulose triacetate, regeneratedproteins, poly(urethanes), poly(arylenes), poly(carbonates) and thelike. Materials having a pore size of several hundredth microns orlarger, or down to several angstroms or smaller. For example, the wallcan comprise regenerated insoluble, nonerodible cellulose, poly(electrolytes) with a pore size of 7 to 50A, epoxy resins,poly(olefins), poly(vinylchlorides) with a pore size of about 50A orless to 150 microns or larger as conventionally made by leaching outincorporated salts, soap micelles, starch or the like materials to givea microporous membrane. Also, the materials that can be used includethose materials having homogeneous properties and microporousproperties, such as cross-linked gelatinous membranes; and the like.

The drug carrier used to form the reservoir is comprised of materials ofnaturally occurring or synthetic origin, of the inorganic or organictypes that do not adversely affect the drug, or the mixture of drugscontained therein and which are permeable to the passage of drug.Generally, the carrier used does not substantially diffuse from thereservoir, but if the carrier does diffuse from the reservoir, forexample if the carrier is an aqueous medium, it would be replaced by acorresponding amount of medium diffusing inward from the exterior of thedevice when the device is positioned in an aqueous type environment.Representative liquid carriers include ethylene glycol, diethyleneglycol, triethylene glycol, propylene glycol, dipropylene glycol,thiodiethylene glycol, ethylene glycol monomethyl ether, ethylene glycolmono-n-butyl ether, ethylene glycol diethyl ether, propylene glycolmono-o-propyl ether, liquid polyethylene glycols having a molecularweight of 200, 300, 400 and 600, 1-3-butylene glycol; solvent systemlauric, ethyl acetate-ethyl alcohol-water 10:83:7; isobutylacetate-isobutyl alcohol-water 24:46:30; mixed binary liquid systemssuch as methanol:water, ethyl alcohol:water, n-amyl alcohol: ethylacetate; mixed tertiary liquid systems such as n-butyl acetate-butylalcohol-water 27:27:46; esters such as liquid methyl propionate, methylisobutyrate, butyl stearate, dibutyl fumurate; fats and oils of plant,animal and marine origin such as almond oil, babassu oil, corn oil,eucalyptus oil, cottonseed oil, olive oil, palm oil, peanut oil,rapeseed oil, soybean oil, tung oil, whale oil, herring oil, saturated,unsaturated, straight and branched chain liquid fatty acids such ascaproic, lauric, arachidic, oleic, linoleic etc.; emulsions of thesingle phase and two phase types such as oil in water, water in oil,lipophilic-liquid-in-hydrophilic-liquid emulsions with or withoutsuspending ingredients; emulsions of castor oil in aqueous solution ofpigskin gelatin, emulsion of gum arabic, water and ethyl cellulose,halogenated hydrocarbons having 2 to 10 carbon atoms, aldehydes andketones having 4 to 10 carbon atoms, syrups, and the like. Othercarriers include silicone oil, medical oil, sterile water; saline;dextrose; dextrose in water or saline; condensation products of castoroil and ethylene oxide combining about 30 to about 35 moles of ethyleneoxide per mole of castor oil; liquid glyceryl triester of a lowermolecular weight fatty acid; oils with emulsifiers such as mono- ordi-glyceride of a fatty acid, or a phosphatide, e.g., lecithin, and thelike; aqueous media in the presence of a suspending agent for xample,sodium carboxymethylcellulose; sodium alginate; poly(vinylpyrrolidone);and the like, alone, or with suitable dispensing agents such aslecithin; polyoxyethylene stearate; and the like, carriers such asacetamide; N,N-dimethyl acetamide, N-(2-hydroxyethyl) acetamide, and thelike. The carrier can also contain adjuvants such as preserving,stabilizing, or wetting agents, and the like.

The rate of release of a drug through various materials can easily bedetermined by those skilled in the art by standard procedures. In thismanner, particular materials used as the device wall as the drug releaserate controlling barrier for release of drug from the reservoirs can beselcted. Various techniques, such as the transmission method, thesorption desorption method, and the like, can be used as measurers ofpermeability. One technique that has been found to be eminently wellsuited is to cast or hot press a film of the material to a thickness inthe range of 2 to 60 mils. The film is used as a barrier between arapidly stirred (e.g., 150 r.p.m.) saturated solution of the drug and arapidly stirred solvent bath, both maintained at constant temperature(typically 37° C). Samples are periodically withdrawn from the solventbath and analyzed for drug concentration. By plotting drug concentrationin the solvent bath versus time, the permeability constant P of thematerial is determined by the Fick's First Law of Diffusion. ##EQU1##wherein Q₁ = cumulative amount of drug in solvent in micrograms at t₁

Q₂ = cumulative amount of drug in solvent in micrograms at t₂

t₁ = elapsed time to first saple i.e.Q₁

t₂ = elapsed time to second sample i.e.Q₂

a = area of membrane in cm²

C = initial concentration of drug

h = thickness of membrane in cm.

By determining the slope of the plot i.e. ##EQU2## and solving theequation using the known or measured values of A, C, and h, thepermeability P constant in cm² /time of the material for a given drug isreadily determined.

Using the above technique, the permeability constant P of progesteronefrom isotonic solution through different materials into isotonicsolution at 37° C as found to be:

    ______________________________________                                        Membrane          Permeability Constant (cm.sup.2 /hr)                        ______________________________________                                        Poly(dimethylsiloxane)                                                                          8.0 × 10.sup.-.sup.2                                  Poly(ethylene)    4.7 × 10.sup.-.sup.4                                  Ethylene vinyl acetate copolymer                                                                3.8 × 10.sup.-.sup.3                                  9% vinyl acetate                                                              Silicone-polycarbonate copolymer,                                                               12.6 × 10.sup.-.sup.3                                 General Electric Mem 213                                                      ______________________________________                                    

Using the above technique and data to design a device of the inventionto release progesterone, one would employ poly(ethylene) as the drugrelease rate controlling material as the wall if a slow rate of releaseis desired, and the cured poly(dimethylsiloxane) membrane as the wall ifa faster rate of release is desired. Both the poly-(ethylene) and thepoly(dimethylsiloxane) are commercially available products. Thepoly(dimethylsiloxane) used above is commercially available Silastic 340of the Dow Corning Co., and the poly(ethylene) is low density with amelt index of 0.85. These examples and like examples can be used todetermine the rate of drug release through different drug releasecontrolling materials by easily ascertained standard techniques known tothe art as recorded in J. Pharm. Sci., Vol 52, pages 1145 to 1149, 1963;ibid. Vol. 53, pages 798 to 802, 1964; ibid. Vol 54 pages 1459 to 1464,1965; ibid. Vol 55, pages 840 to 843 and 1224 to 1239; 1966; Encyl.Polymer Sci. Technol., Vol 5 and 9, pages 65 to 82 and 794 to 807, 1968;the references cited therein, and the like.

The rate of solubilization, or the rate at which drug will go intosolution is quantitatively governed by physico-chemical principles. Foran example, a drug particle dispersed in a solvent is surrounded by athin layer of solvent having a finite thickness l in cm. This layer isconsidered as an integral part of the drug and it is characteristicallyreferred to as the "stagnant layer." The stagnant layer remains a partof the surface of the drug, moving wherever the drug moves. Using Fick'sFirst Law of Diffusion, the rate of solution is the rate at which adissolved drug diffuses through the stagnant layer for supplying drug tothe reservoir's inner wall. The driving force behind the movement of thedrug through the stagnant layer is the difference in concentration ofthe drug, C₁, in the stagnant layer at the surface of the drug and theconcentration C₂ on the farthest side of the stagnant layer. Thedifference in concentration C₁ -C₂ determines the rate at which drug issolubilized in the carrier. Hence, if the carrier on the farthest sideconains its optimum concentration because of a low release by the drugrelease rate controlling wall, the rate of solubilization of new drugwill be low. Correspondingly, as drug leaves the carrier new drug issolubilized to establish a steady state within the carrier.

The rate of diffusion of a drug in a solubilizing limited carrier isbroadly determined by measuring the rate a drug transfers from onechamber through a sintered glass filter of known pore size and thicknessinto another chamber and calculating from the obtained data the drugtransfer rate. The method is carried out by adding to a first conicalflask equipped with a ground glass stopper and a stirring bar, ameasured amount of carrier and simultaneously, the drug in the samecarrier is added to a second conical flask while keeping the level ofthe carrier in the two flasks the same. Next, the flasks are stirred,and samples drawn at various time intervals for analysis. The measuredrate of drug transport through the sintered glass filter, and theconcentration difference of the drug in the two flasks is thencalculated. These procedures are known to the art in Proc. Roy. Sci.London, Ser. A, Vol. 148, page 1935; J. Pharm Sci., Vol. 55, pages 1224to 1229, 1966; and references cited therein. The diffusion coefficientof a drug can also be experimentally determined by using the aboveapparatus or similar apparatus and procedures as described in Diffusionin Solids, Liquids and Gases, by W. Jost, Chapter XI, pages 436 to 488,1960, Revised Edition, Academic Press Inc., New York.

Also, according to Fick's Law, the rate of drug solution is directlyporoportional to the area of the drug, A in cm², as exposed to carrierand inversely proportional to the length of the path through which thedissolved drug molecule must diffuse. Then, the rate of solution of thedrug is given by ##EQU3## wherein R is the rate of solution, D is aproportionality constant called diffusion coefficient in cm² /sec, andC₁, C₂, and l are as previously defined. See Remington PharmaceuticalScience, 14th Ed., pages 246 to 269, 1970, Mack Publishing Company.

The solubility of the drug in the drug release rate controlling materialcomprising the wall of a device broadly is determined by preparing asaturated solution of a given drug and ascertaining, by analysis, theamount present in a definite area of the material. For example, thesolubility of the drug in the wall is determined by first equilibratingthe wall material with a saturated solution of the drug at a knowntemperature, for example 37°° C, or with a pure liquid drug, if the drugis a liquid at 37° C. Next, drug is desorbed from the saturated wallmaterial with a suitable solvent for the drug. The resultant solutionfor the drug then is analyzed by standard techniques such asultraviolet, visible spectrophotometry, refractive index, polarography,electrical conductivity and the like, and calculating from the data theconcentration, or solubility of the drug in the material.

The solubility of a drug in a liquid core carrier can be determined byvarious art known techniques. One method consists in preparing asolution, i.e. a carrier, of the given drug and ascertaining by analysisthe amount of drug present in a definite quantity of the carrier. Asimple apparatus for this purpose consists of a test tube of medium sizefastened upright in a water bath maintained at constant temperature. Thecarrier and drug are placed in the tube and stirred by means of a motordriven rotating glass spiral. After a given period of stirring, adefinite weight of the carrier is analyzed and the stirring continuedfor an additional period of time. If the analysis shows no increase ofdissolved substance after the second period of stirring, the results aretaken as the degree of solubility of the drug in the carrier. Numerousother methods are available for the determination of the degree ofsolubility of a drug in a liquid carrier. Typical methods used for themeasurement of solubility are chemical analysis, measurement of density,refractive index, electrical conductivity, and the like. Details ofvarious methods for determining solubilities are described in UnitedStates Public Health Service Bulletin No. 67 of the Hygienic Laboratory;Encyclopedia of Science and Technology, Vol 12, pages 542 to 556, 1971McGraw-Hill, Inc; Encyclopaedic Dictionary of Physics, Vol 6; pages 545to 557, 1962, Pergamon Press, Inc; and the like.

Using the procedures and formulas above described, one skilled in theart can design a drug delivery device according to the inventon byascertaining the properties of the wall and carrier forming material andthen fabricating a drug delivery device by selecting a carrier in whichthe drug has limited solubility and which is permeable to the drug butat a lower rate than the permeability of the wall. For example, by usingthe permeability coefficient, which is determined by using theprocedures and formulas, and which permeability coefficient is definedas the product of the diffusion coefficient, D_(w), of the drug in thewall and a distribution coefficient, K, which is a ratio of thesolubility of the drug in the wall to the solubility of the drug in thesaturated solution, the selection of materials for forming the wall andthe carrier can be made for making a device according to the invention.For purposes of comparing the permeability of the wall to that of thecarrier, it is convenient to define the permeability as follows: P_(w) =PC = D_(w) S_(w) wherein P, C and D_(w) have the meaning as abovedescribed and S_(w) is the solubility of the drug in the wall. Thepermeability of the wall carrier to the drug can similarly be defined asP_(c) = D_(c) S_(c) wherein D_(c) and S_(c) are the diffusioncoefficient and the solubility of the drug in the liquid core carrier.The solubility, S_(c), can be determined by methods previously cited.The diffusion coefficients of drug in liquid carriers will be in therange of 10.sup.⁻⁶ to 10.sup.⁻⁵ cm² /sec. The diffusion coefficient ofthe drug in the wall will be in the range of 10.sup.⁻¹⁰ to 10.sup.⁻⁸ cm²/sec. Thus, a selection of carrier materials such that P_(c) > P_(w),preferably P_(c) ≧ 5 P_(w), is ascertained for preparing a drug deliverydevice. The symbol ">" means greater than and the symbol "≧" meansgreater than or equal to.

By using the above described techniques, the degree of solubility ofvarious drugs in select carriers is ascertained as follows:N-methyl-N-2-propylbenzlamine hydrochloride very slightly soluble inwater; isoamyl nitrite miscible with alcohol; pentaerythrioltetranitrate diluted with lactose slightly soluble in alcohol;isoxsuprine hydrochloride slightly soluble in mixture of water andalcohol; levonordefrin slightly soluble in ketones; pralidoxine chloridesparingly soluble in methanol; phenoxybenzamine hydrochloride sparinglysoluble in water; bendroflumethiazide practically insoluble in water;methyclothiazide sparingly soluble in methanol, slightly soluble inalcohol and very slightly soluble in water and isopropyl alcohol;triamterene sparingly soluble in 2-methoxyethanol and very slightlysoluble in dilute mineral acids; ergotamine slightly soluble in water inpresence of slight excess of tartaric acid; desoxycorticosterone acetatesparingly soluble in dioxane and slightly soluble in vegetable oils;estradiol sparingly soluble in vegetable oils; estradiol valeratesparingly soluble in sesame oil and peanut oil; dienestrol slightlysoluble in fatty oils; ethynodiol diacetate sparingly soluble in fixedoils; progesterone sparingly soluble in vegetable oils; nikethamidemiscible with water; flurothyl miscible with propylene glycol; and thelike.

In the specification and the accompanying claims, the term, "drug",broadly includes physiologically or pharmacologically active substancesfor producing a localized or systemic effect or effects in mammalsincluding humans and primates; avians such as chicken and turkeys;valuable domestic household, sport or farm animals such as horses, dogs,cats, cattle, sheep and the like; or for administering to laboratoryanimals such as mice, monkeys, rats, guinea pigs; and the like. That is,the novel drug delivery device can be used for administering drugs thatare physiologically or pharmacologically active at a point in nearrelation to the drug delivery device, or, for administering asystemically active drug which will produce a physiological orpharmacological response at a site remote from the point of applicationof the drug delivery device. The active drugs that can be administeredby the drug delivery device of the invention include, withoutlimitation: for example, drugs acting on the central nervous system suchas, hypnotics and sedatives such as pentobarbital sodium, phenobarbital,secobarbital, thiopental, etc.; heterocyclic hypnotics such asdioxopiperidines, and glutarimides; hypnotics and sedatives such asamides and ureas exemplified by diethylisovaleramide andα-bromoisovaleryl urea and the like; hypnotics and sedative alcoholssuch as carbomal, naphthoxyethanol, methylparaphenol and the like; andhypnotic and sedative urethans, disulfanes and the like; psychicenergizers such as isocarboxazid, nialamide, phenelzine, imipramine,tranylcypromine, pargylene and the like; tranquilizers such aschloropromazine, promazine, fluphenazine reserpine, deserpidine,meprobamate, benzodiazepines such as chlordiazepoxide and the like;anticonvulsants such as primidone, diphenylhydantoin, ethotoin,pheneturide, ethosuximide and the like; muscle relaxants andanti-parkinson agents such as mephenesin, methocarbomal,trihexylphenidyl, biperiden, levo-dopa, also known as L-dopa andL-β-3-4-dihydroxyphenylalanine, and the like; analgesics such asmorphine, codeine, meperidine, nalorphine and the like; anti-pyreticsand anti-inflammatory agents such as aspirin, salicylamide, sodiumsalicylamide and the like; local anesthetics such as procaine,lidocaine, naepaine, piperocaine, tetracaine, dibucaine and the like;antispasmodics and anti-ulcer agents such as atropine, scopolamine,methscopolamine oxyphenonium, papaverine, prostaglandins such as PGE₁,PGE₂, PGF₁.sub.α,PGF₂.sub.α, PGA and the like; anti-microbials such aspenicillin, tetracycline, oxytetracycline, chlorotetracycline,chloramphenicol, sulfonamides and the like; anti-malarials such as4-aminoquinolines, 8-aminoquinolines and pyrimethamine; hormonal agentssuch as prednisolone, cortisone, cortisol and triamcinolone; androgenicsteroids, for example, methyltestosterone, fluoximesterone and the like;estrogenic steroids, for example, 17β-estradiol and ethinyl estradiol;progestational steroids, for example 17α-hydroxyprogesterone acetate,19-nor-progesterone, norethindrone and the like; sympathomimetic drugssuch as epinephrine, amphetamine, ephedrine, norephinephrine and thelike; cardiovascular drugs, for example, procainamide, amyl nitrate,nitroglycerin, dipyridamole, sodium nitrate, mannitol nitrate and thelike; diuretics, for example, chlorothiazide, flumethiazide and thelike; antiparasitic agents such as bephenium hydroxynaphthoate anddichlorophen, dapsone and the like; neoplastic agents such asmechlorethamine, uracil mustard, 5-fluorouracil, 6-thioguanine,procarbazine and the like; hypoglycemic drugs such as insulins,protamine zinc insulin suspension, globin zinc insulin, isophane insulinsuspension, and other art known extended insulin suspensions,sulfonylureas such as tolbutamide, acetohexamide, tolazamide, andchlorpropamide, the biguanides and the like; nutritional agents such asvitamins, essential amino acids, essential fats and the like; and otherphysiologically or pharmacologically active agents. Also, the drugs canbe present as the pharmacologically acceptable derivatives, such asethers, esters, amides, acetals, etc. that lend themselves to passageinto the circulatory system. For highly water soluble drugs, it ispreferable that the wall or the reservoir, or both be formed from amaterial that is substantially impermeable to water to essentiallyprevent dilution of the drug by absorption of body fluids into thedevice with an accompanying decrease in drug release rate. Thesederivatives can be prepared by art known techniques and then used in thepractice of the invention. Of course, the drug derivative should be suchas to convert to the active drug within the body through the action ofbody enzymes assisted transformations, pH, specific organ activities,and the like.

The amount of drug present in the reservoir, whether dissolved,partially dissolved or undissolved, is generally non-limited and it isan amount equal to or larger than the amount of a drug that on itsrelease from the device is effective for bringing about the drug'sphysiological or pharmacological local or systemic effects. For example,the amount of drug present in the reservoir of a drug delivery devicewhen the device is used for a period of time to achieve local orsystemic effect is for various drugs, such as 11-desmethoxyreserpineabout 5 to 40 mg in the reservoir; for acetophenazine an amount in thereservoir of 100 to 200 mg; for methoxypromazine about 600 to 750 mg inthe reservoir; for emcylamate a reservoir amount of 1.5 to 2.0 gm; forphenylglycodol a reservoir amount of 1.5 to 1.9 gm; about 160 to 250 mgof butabarbital in the reservoir; about 150 to 170 mg ofchlorodiazepoxide; from 0.5 to 1.2 gm of methsuximide; from 0.7 to 1.9gm of ethosuximide; from 20 to 40 mg of hydrolazine; about 50 to 100 mgof totazoline; and the like. Generally, the drug delivery devices madeaccording to the invention can contain from about 250 nanograms to 50grams of drug for releasing it at a controlled rate of from about 25nanograms to about 25 grams of drug or larger amounts per day. Ofcourse, other devices containing different amounts of drug for use fordifferent time periods such as week, month and year are also readilymade by the invention.

It will be appreciated by those versed in the art that the unique drugdelivery device of this invention can provide for the programmeddelivery of drug at a rate of delivery characterized by a zero ordertime dependence for prolonged period of time; and, that the devicetherefore lends itself to administering an effective amount of drugneeded for a therapeutic effect while essentially avoiding the presenceof excessive amount of drug at the needed biological site. By aprolonged period of time is meant, as used herein, periods that embracethe time needed for a fast acting drug to effect its end up to periodsthat embrace the continual, uninterrupted, repititious time of a longterm drug delivery device. For example, the prolonged time can be 1 houror more for drugs, like local anesthetics, analgesics, prostaglandins orthe like, that are effective in nanogram and milligram amounts, or thelike, to 3 years or longer for steriods released within the uterinecavity. Other examples include wherein the amount of drum in thereservoir can be 100 to 300 mg of thiopropzate for releasing 15 to 30 mgover a 24 hour period; 200 to 400 mg in the reservoir ofphenyltoloxamine for a release of 150 to 200 mg per day; 100 to 200 mgof papaverine in the reservoir for a topical release 30 to 75 mg over a24 hour period; 2.5 g to 4.0 g of mephenoxalone for a release of 1.0 to1.5 g per day; 15 to 25 mg of tranylcypromane for a release of 10 to 15mg as the standard dose; 1 to 2 gm of trimethadione present in thereservoir for a release administration of 0.5 to 1.0 g per day;prostaglandins for example PGE₁, PGE₂, PGA₁, PGF₂.sub.α in amounts of0.5 mg to 10 mg for release of 1 ng to 100 ng and the like; forprogestogen or progesterone the administration in the uterus of 10 to200 μg per day for release for 1 year to 3 years as an anti-fertilityagent in a mature, child-bearing woman; an oral device administering 300mg to 600 mg per day of analgesic acetaminophen to a 60 to 70 kg adultmale; and the like.

The reservoir comprising the liquid core and the drug is fabricated bystandard techniques. For example, in one embodiment the liquid can bemixed with the drug in solid, semi-solid, or liquid forms at the time ofmixing, and then distributed therethrough by conventional methods, suchas ballmilling, calendering, stirring, shaking, roll-milling, and thelike. The liquid core is then charged into a drug release ratecontrolling material and sealed therein. In another embodiment theliquid core and the drug are mixed and then charged into a highlypermeable tube that is positioned within a drug release rate controllingmaterial. Alternatively, the tube can be coated with the release ratematerial, or a prepolymer can be case around the tube and finally curedinto a drug release rate controlling material. The wall material formingthe device and having the reservoir contained therein can be formed to agiven drug design by molding, casting, pressing, extruding, drawing,rotational molding, compression and transfer molding, or like standardprocesses of manufacture. Also, depending on the material used to formthe wall, a monomers may be cured at this stage of manufacture. Theability to design and shape the wall into tubes, rods, discs, films,rings and other highly reproducible shapes of controllable composition,readily results in fabrication of drug delivery devices with controlledcharacteristics and thus overcomes a significant disadvantage ofpreviously described devices. Other standard procedures, as described inModern Plastics Encyclopedia, Vol. 46, pages 62 to 70, 1969, well knownto those skilled in the art can be used to fabricate the drug deliverydevice of the invention.

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, drawings and the accompanying claims.

EXAMPLE 1

A drug delivery device comprising a reservoir containing a drug and aliquid core surrounded by a drug release rate controlling wall permeableto the passage of drug is manufactured as follows: first, a reservoircomprised of a liquid dispersion consisting of 11% by weight ofprogesterone and 10% by weight of barium sulfate in a mixture consistingof 3 parts by weight of Dow-Corning Silastic 382 elastomer resin liquidsilicone oil and 1 part by weight of Dow-Corning 360 medical gradesilicone oil are thoroughly mixed in a standard laboratory v-blender toyield a liquid dispersion. The progesterone is sparingly soluble in theliquid dispersion. Next, an aliquot of the liquid dispersion is injectedinto a section of medical grade polyethylene tubing having an outsidediameter of 0.110 inches and an inside diameter of 0.070 inches and theend of the tubing heat sealed with a standard, hand heater. The filledpolyethylene tubing, about 10 cm in length, then is placed into thelower half of a two piece triangular shaped mold, the upper half isplaced thereon, and the mold electrically heated to yield a triangularshaped drug delivery device. The device will release about 25 to 30micrograms of progesterone per day for controlling fertility in an adultwoman.

EXAMPLE 2

A drug delivery implant device comprised of a drug release ratecontrolling wall permeable to the passage of drug and surrounding areservoir comprised of a drug and a liquid core for releasingprogesterone for cattle is manufactured as follows: a liquid dispersiondrug carrier is prepared by intimately contacting and blending in arotating mill 25% by weight of progesterone and 10% by weight of bariumsulfate with a mixture comprising 3 parts by weight of Dow-Corning 382elastomer resin, low molecular weight prepolymer liquid silicone and 1part by weight of Dow-Corning 360 medical fluid silicone oil to yield aliquid dispersion. The liquid dispersion is permeable to the drug andthe drug is sparingly soluble therein. Next, the liquid dispersion isinjected into a length of ethylene vinyl acetate copolymer tubingcomprised of 9% by weight of vinyl acetate and having an inside diameterof 0.075 inches and an outside diameter of 0.110 inches. The ends of thetubing are heat sealed and the tubing is then formed into an open ringby means of a heated mold. The device releases 90 to 100 micrograms ofprogesterone per day.

EXAMPLE 3

Following the procedure set forth in Example 1, a drug reservoircomprised of a liquid core containing aqueous poly(vinyl pyrrolidone)and progesterone housed within a poly(ethylene) barrier is prepared bygenerally following the example. The drug is sparingly soluble in theaqueous poly(vinyl pyrrolidone) and both the poly-(vinyl pyrrolidone)and the poly(ethylene) are permeable to the passage of the steroid, butthe rate of passage is lower for the poly(ethylene). The poly(ethylene)barrier has a thickness of 50 microns, and it releases about 33micrograms per square centimeter per day of progesterone to a drugreceptor site.

EXAMPLE 4

A drug delivery device shaped like an elongated, end-tapered tablet andcomprised of a liquid carrier of aqueous carboxymethylcellulosecontaining progesterone laminated between two poly(ethylene) sheets,sealed at their perimeters, and having a thickness of 50 microns isprepared according to the procedure of Example 1. The steroid, in thisdevice, is sparingly soluble in the carrier, and both the carrier andthe poly(ethylene) are permeable to the passage of the steroid, with therate of passage for the former higher than the rate of passage of thelatter. The use of this device results in a controlled, rate of releaseof progesterone over a prolonged period of about 1 year at the rate of33 micrograms per sq. cm. per day.

Example 5

Repeating the general procedure as described in Example 1, a drugdelivery device is made of a drug permeable, release rate controllingwall of ethylene vinylacetate copolymer of 91% ethylene and 9% vinylacetate of about 50 microns thick and surrounding a reservoir comprisedof progesterone in water is made by substituting the ingredients of thisexample for those set forth above. A drug delivery device made accordingto this procedure will release about 230 micrograms of progesterone persq. cm. per day.

EXAMPLE 6

A drug delivery device suitable for use as a tampon is comprised of aninsoluble, durg permeable, ethylene vinyl acetate elastomer wall shapedas an elongated cylinder defining a discrete, hollow reservoir. Thereservoir is filled with hydrocortisone in a very slightly solublecarrier. The carrier is prepared by adding hydrocortisone to waterlightly charged with methyl cellulose. After the reservoir is filled,the wall is closed. Positioning of the drug delivery device within thecavity results in the metering of hydrocortisone through the copolymerwall to the environment at a controlled rate during the used period ofthe device.

EXAMPLES 7 to 14

Other drug delivery devices made according to the procedure set forth inthe disclosure and the previous examples include the following drugdelivery devices containing 10 to 90% of drug in a carrier phase withina drug delivery device: comprising phenazocine hydrochloride insparingly soluble water carrier encased within plasticized poly(vinylchloride); an intrauterine drug delivery device comprised of the drugprogesterone, the carrier water in the reservoir with a wall comprisedof ethylene vinyl acetate copolymer wherein the vinyl acetate is 33% ofthe copolymer; the device as just described wherein the wall is formedfrom finely ground radiation cross-linked poly(cis-1,4-polyisoprene); anocular insert drug delivery device consisting of pilocarpine in asparingly soluble mixture enclosed in ethylene vinyl acetate copolymercomprising 18% vinyl acetate; a drug delivery device comprising anon-thrombogenic hydrocephalus shunt consisting of a heparin in asolubilizing limited carrier phase and surrounded with a wall ofinsoluble polyester; a drug delivery device for oral use shaped as adrug administering elastic rubber band wherein the reservoir contains adrug in a sparingly soluble carrier surrounded with poly(ethylene); adrug delivery device designed as a Stan-Edwards heart valve comprisinghigh density poly(ethylene) around a drug reservoir; and, a drugdelivery device manufactured as a suture comprising a wall formed of apolyamide encapsulated around a reservoir of drug and carrier.

It will be understood to those versed in the art in the light of thepresent specification, drawings and accompanying claims that theinvention makes available to the art both a novel and useful drugdelivery device for administering a drug to produce a local or systemicphysiologic or pharmacologic effect; as, the rate of release of drugadministered from the device can be controlled to produce these effects,while simultaneously lessening or overcoming the undesirable effectsfrequently associated with the administration of drugs by prior artmethods. It will be further understood to those versed in the art thatmany different embodiments of this invention can be made withoutdeparting from the spirit and the scope of the invention. Accordingly,it is to be understood that the invention is not to be construed aslimited, but it embraces all equivalents inherent therein.

I claim:
 1. A delivery device for the controlled and continuousadministration of drug to a body site over a prolonged period of time,said device comprising:a. a means for containing and releasing the drugat a controlled rate comprising a reservoir containing a dissolved drugportion and an undissolved replacement drug portion in a liquid carriermaterial permeable to the passage of the drug therethrough, said drughaving limited solubility in said liquid carrier material; thereplacement drug portion being present in an amount in excess of itssolubility in the carrier material and in an amount sufficient tomaintain the amount of the dissolved drug portion substantially constantduring said prolonged period of time, said means further comprising: b.a shaped wall that surrounds the reservoir and is characterized by beinginsoluble in body fluid, maintaining its integrity during said prolongedperiod of time, and by being formed at least in part of a microporouspolymer housing in its micropores a drug release rate controlling mediumpermeable to the passage of the drug but having a lower permeability tothe drug than the permeability of the liquid carrier material to thedrug; so that the device when placed at the body site, continuouslyreleases drug from the reservoir of the body site at a physiologicallyor pharmacologically effective controlled rate by metered passagethrough the medium, the dissolved drug so released being replaced by thecontinuous dissolving of replacement drug in the carrier material so asto substantially maintain the amount of dissolved drug in the reservoirsubstantially constant during said prolonged time period.
 2. A deliverydevice in accordance with claim 1 wherein the cumulative amount ofdissolved drug and undissolved drug contained in the liquid carriermaterial is in an amount to provide a complete dosage regimen for aliving organism for a period of time in an amount of at least 1 month.3. A delivery device in accordance with claim 1 wherein the drug issoluble in the liquid carrier material in an amount of one part of drugto about 10 to 15,000 parts of liquid carrier material at 25° C.
 4. Adelivery device in accordance with claim 1 wherein the permeability ofthe liquid carrier material to drug is from about 100:1 to 2:1 timesgreater than the permeability of the medium in the micropores of thewall.
 5. A delivery device in accordance with claim 1 wherein the drugrelease rate controlling medium material is permeable to the passage ofdrug by diffusion.
 6. A delivery device in accordance with claim 1wherein the rate of controlled and continuous release from the device issubstantially independent of time.
 7. A delivery device in accordancewith claim 1 wherein the prolonged period of time is at least a periodof 1 month.
 8. A delivery device in accordance with claim 1 wherein thedrug is metered in vivo from the device to an internal receptor site ofa body cavity of a mammal.
 9. A delivery device in accordance with claim1 wherein the permeability of said medium to said drug is such that therate of flow of drug from the reservoir is less than the rate ofclearance of migrated drug from the external surface of the device whenthe device is in contact with body tissues or fluids.
 10. A deliverydevice in accordance with claim 1 wherein the device is an intrauterinedevice said environment of use being the uterus of a female mammal.